WO2008107373A1 - Antagonistes du récepteur de minéralocorticoïde pour le traitement de l'endométriose - Google Patents

Antagonistes du récepteur de minéralocorticoïde pour le traitement de l'endométriose Download PDF

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Publication number
WO2008107373A1
WO2008107373A1 PCT/EP2008/052456 EP2008052456W WO2008107373A1 WO 2008107373 A1 WO2008107373 A1 WO 2008107373A1 EP 2008052456 W EP2008052456 W EP 2008052456W WO 2008107373 A1 WO2008107373 A1 WO 2008107373A1
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WO
WIPO (PCT)
Prior art keywords
receptor antagonists
receptor
endometriosis
estrogen
treatment
Prior art date
Application number
PCT/EP2008/052456
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German (de)
English (en)
Inventor
Carsten Moeller
Ulrike Kaufmann-Reiche
Anja Schmidt
Ulrike Fuhrmann
Oliver-Martin FISCHER
Original Assignee
Bayer Schering Pharma Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Schering Pharma Aktiengesellschaft filed Critical Bayer Schering Pharma Aktiengesellschaft
Priority to EP08717238A priority Critical patent/EP2131825A1/fr
Priority to CA002679520A priority patent/CA2679520A1/fr
Priority to JP2009551220A priority patent/JP2010520178A/ja
Priority to MX2009009332A priority patent/MX2009009332A/es
Priority to BRPI0808427-0A priority patent/BRPI0808427A2/pt
Priority to US12/529,447 priority patent/US20110003778A1/en
Priority to AU2008223859A priority patent/AU2008223859A1/en
Publication of WO2008107373A1 publication Critical patent/WO2008107373A1/fr
Priority to IL200380A priority patent/IL200380A0/en
Priority to ZA2009/06849A priority patent/ZA200906849B/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of mineralocorticoid receptor antagonists for the treatment of endometriosis.
  • the present invention relates to a better therapeutic agent against endometriosis, which shows a better effect or side effect profile than previously available treatment therapies.
  • endometriosis is a dislocation of endometrial tissue outside the uterine cavity. These so-called endometriotic lesions nest at different sites of the peritoneal cavity, e.g. the intestinal wall, on the ovary or rectovaginal and maintain the properties of their original tissue. Endometriosis is essentially inflammatory and affects 10-20% of women of reproductive age. The core symptoms of endometriosis are chronic abdominal pain, dysmenorrhea, dyspareunia, dysuria, bleeding disorders and infertility. The symptoms are mostly combined. It is assumed that the lesions pass through the fallopian tube into the peritoneal space through retrograde menstruation and then settle there.
  • GnRH agonists suppress endogenous estrogen production by interfering with the hypothalamic / pituitary / ovarian axis. This leads to a reduction in estrogen levels to postmenopausal levels and, concomitantly, a reduction in endometriosis-related symptoms. Androgens work similarly, with an additional direct effect on the ovary is postulated. Due to their side-effect profile, both therapeutic approaches are only suitable for short-term use (6-9 months).
  • GnRH agonists induce postmenopausal symptoms such as hot flashes and decreased bone mass. Acne, weight gain and irreversible mood swings can also be observed with androgens.
  • Depot-MPA medroxyprogesterone acetate
  • endometriosis can be treated by surgical removal of the endometriotic lesions in a laparoscopic procedure.
  • the relapse rate after such an intervention is very high (25-30%).
  • Hysterectomy ie the complete removal of the uterus, is the final therapy option in such particularly stubborn cases.
  • the object of the present invention is to provide new therapeutic approaches for the treatment of endometriosis, which show a better effect or side effect profile than previously available treatment therapies.
  • the therapeutic approach according to the invention is intended to make possible a long-term or long-term treatment of endometriosis.
  • the present invention solves the problem with a new therapeutic approach for the long-term treatment of endometriosis.
  • mineralocorticoid receptor antagonists are used for the preparation of a medicament for the treatment of endometriosis.
  • the duration of treatment with the mineralocorticoid receptor antagonist can over a
  • the mineralocorticoid receptor antagonists may be used alone or in combination with other substances.
  • SPRMs Selective Progesterone Receptor Modulators
  • Estrogen receptor isotype-specific ligands (ER- ⁇ ligands)
  • This invention also relates to the use of compounds which combine their anti-mineralocorticoid activity with action on other receptors for the manufacture of a medicament for the treatment of endometriosis.
  • Mineralocorticoid receptor antagonists are substances which have a binding affinity to the mineralocorticoid receptor and inhibit the action of the natural mineralocorticoid aldosterone. Examples include the compounds spironolactone, Epleronone and drospirenone.
  • the mineralocorticoid receptor antagonists to be used according to the invention should have a binding affinity at the mineralocorticoid receptor which is approximately equal to or better than that of the aldosterone.
  • Mineralcorticoid receptor antagonists are only those substances that block the aldosterone at its receptor, but not those that inhibit the endogenous production of aldosterone
  • progestins are understood to be either the natural progesterone itself or synthetic derivatives which, like the progesterone itself, bind to the progesterone receptor and inhibit ovulation in dosages which are above the ovulation inhibitor dose.
  • synthetic derivatives include drospirenone, gestodene, levonorgestrel, cyproterone acetate, desogestrel and 3-ketodesogestrel, norethisterone, norethisterone acetate and dienogest.
  • SERMs Selective Estrogen Receptor Modulators
  • SERMs are compounds which either have an antiestrogenic or estrogenic effect on the tissue, for example inhibit the action of the estrogen on the uterus but have a neutral or estrogen-like effect on the bone.
  • examples include tamoxifen, raloxifene and basidoxifen.
  • SPRMs Selective Progesterone Receptor Modulators, sometimes also referred to as mesoprogestins
  • SPRMs are compounds which have both agonistic and antagonistic activity in vivo on the progesterone receptor. Like progesterone and progesterone receptor antagonists, the SPRMs show a high binding affinity to the progesterone receptor. However, the SPRMs have other pharmacodynamic properties compared to the progestins or progesterone receptor antagonists.
  • Progesterone agonist activity determined in vivo by common biological tests (for example, in the McPhail Test, Selye, H.) of SPRMs is the fundamental property of these compounds. However, this activity lags behind that of progesterone.
  • SPRMs antagonize the action of progesterone.
  • the maximum antagonizing effect is less than that which can be induced by RU 486 or another pure progesterone antagonist.
  • the WO Referenced 01/15679 for further embodiments, for example, the WO Referenced 01/15679.
  • Typical representatives of this class of compounds are 4- [17 ⁇ -methoxy-17 ⁇ - (methoxymethyl) -3-oxoestra-4,9-dien-11 ⁇ -yl] benzaldehyde (1E) -oxime, 4- [17 ⁇ -
  • SARMs are substances which have a tissue-selective androgenic or anti-androgenic action, such as anti-androgenic effects on the skin, but have no or positive effect on libido.
  • Combinations of progestogens and estrogens are the active ingredient combinations contained in the conventional oral contraceptives, for example, Yasmin, Femovan, Triquilar, Marvelon, YAZ, etc.
  • Progesterone receptor antagonists are compounds that inhibit the action of progesterone on its receptor.
  • RU486, onapristone and 1-1 ⁇ - (4-acetylphenyl) -17 ⁇ -hydroxy-17 ⁇ - (1,1,2,2,2,2-pentafluoroethyl) estra-4,9-dien-3-one WO 98/34947.
  • Estrogen receptor antagonists are compounds that block the action of the estrogen on its receptors (estrogen receptor ⁇ and estrogen receptor ⁇ ).
  • the estrogen receptor ⁇ blocking compound is, for example, 7 ⁇ - [9- (4,4,5,5,5-pentafluoropentylsulfinyl] -n-nonyl] -estra-1, 3,5 (10) -triene-3,17 ⁇ - to call diol.
  • Glucocorticoids are compounds which induce agonistic action on the glucocorticoid receptor and thus have an immunosuppressive effect.
  • the dexamethasone is mentioned.
  • the mineralcorticoid receptor antagonists are used in the following dosages:
  • Spironolactone 10 to 500 mg / d and person, single dose or in 2 halves, preferably 25 to
  • mineral corticosteroid receptor antagonists are used in equivalent dosages, that is dosages comparable to those of the above compounds in the treatment of endometriosis.
  • mineralocorticoid receptor antagonists are used together with another compound (see above), these compounds will be used in the dosage ranges already described for these other compounds.
  • mineralcorticoid receptor antagonists and any further compounds to be used are formulated in a manner known to the person skilled in the art.
  • the classic physiological function of aldosterone as an effector of the renin-angiotensin-aldosterone system is the regulation of extracellular volume and the homeostasis of the potassium balance.
  • Activation of the mineralocorticoid receptor may occur in various tissues which exhibit expression of the mineralocorticoid receptor, such as e.g. the brain, the heart or blood vessels, lead to pathological phenomena. Examples include hypertension, vascular diseases, renal failure, migraine, neuropathy, retinopathy, baroreceptor dysfunctions, liver diseases and edema called. It is postulated that these harmful effects of aldosterone by the mineralocorticoid receptor in the non-classical target organs, such. As the blood vessels are caused (Rudolph et al., 2004).
  • the effect of the aldosterone on the target organ kidney results in the action of the diuretics spironolactone and epleronone: they increase renal sodium excretion in the presence of aldosterone and reduce potassium excretion. This leads in total to an increased water excretion. They are therefore used in the treatment of hypertension (Weinberger et al., 2002, Weinberger et al., 2005).
  • the inhibition of aldosterone with the help of substances such as Epleronon also has a protective effect on various target organs, without this being accompanied by a measurable reduction in blood pressure or without having a diuretic effect (Rudolph et al., 2004).
  • the animal model e.g.
  • the mineralocorticoid receptor surprisingly has a changed expression profile in endometriosis. This can be determined, for example, by quantitative RT-PCR, in which the mRNA content is measured in comparison to a reference gene.
  • the mineralocorticoid receptor shows a 2 to 3 times higher mRNA content when compared to the healthy tissue, the endometrium of the uterus (see Figure 1).
  • One embodiment of the invention contemplates the use of a combination of mineralocorticoid receptor antagonists with at least one of progesterone, progesterone receptor antagonists, glucocorticoids, a combination of progestogens and estrogens, SERMs, SPRMs, and estrogen receptor isotype-specific ligands (selective ER ⁇ agonists)
  • progesterone progesterone receptor antagonists
  • progesterone receptor antagonists glucocorticoids
  • a combination of progestogens and estrogens SERMs, SPRMs, and estrogen receptor isotype-specific ligands (selective ER ⁇ agonists)
  • a combination of a mineralocorticoid receptor antagonist with one of these already known principles of action should on the one hand have an additive effect in the effect, on the other hand, however, also allow a long-term application.
  • the substances added in addition to the mineralocorticoid receptor antagonist should be used in the pharmacologically effective dosages already described.
  • SPRMs and progesterone receptor antagonists in a dose range of 1 mg to 100 mg per woman per day, with glucorticoids of 0.01 - 2 mg / kg and day.
  • mineralocorticoid receptor antagonists which simultaneously show either a gestagenic effect, or have a progesterone receptor antagonist activity or a glucocorticoid effect or an estrogen receptor isotype-specific activity.
  • the application of the mineralcorticoid receptor antagonists can be carried out continuously and discontinuously in all cases.
  • Antagonist is administered daily in oral form.
  • mineral corticoid receptor antagonists and progestins are particularly preferred, mineral corticoid receptor antagonists and progesterone receptor antagonists and mineralocorticoid receptor antagonists and combinations of estrogens and
  • Treatment schemes are preferred in which the gestagens are given continuously in daily doses.
  • Estrogens and progestins can be given either continuously or discontinuously. With discontinuous administration, especially 21/7 or 24/4 cycles are preferred.
  • progestagens are the compounds medroxyprogesterone acetate, cyproterone
  • Combinations is preferred as estrogen the compound ethinyl estradiol.
  • Receptors show, in particular compounds are preferred, in addition to progesterone
  • Receptor are active, or in addition to the androgen receptor as antagonists are active.
  • mineral corticoid receptor antagonists which show a gestagenic effect at the same time.
  • Treatment regimens containing a daily oral dose are particularly preferred.
  • Mineralcorticoid receptor antagonists that also have a gestagenic effect can also be given in conjunction with estrogens.
  • estrogen is ethinyl estradiol.
  • Such combinations may be given either continuously (daily) or in a discontinuous regimen.
  • discontinuous treatment regimens are those which provide an application of 24 days followed by a break of 4 days, or those which follow a treatment of 21 days followed by a break of 7 days. Breaks in these
  • Treatment regimens can be done either by giving placebos or by simple treatment interruption.
  • Example 1 The invention will be explained in more detail with reference to the following examples 1 to 3 and the accompanying figures 1 to 3, without wishing to restrict the invention to these examples.
  • Example 1 Example 1 :
  • the expression of the mineralocorticoid receptor in human endometriotic lesions was compared to that in the normal human endometrium.
  • the mineral corticoid receptor DNA was isolated from the corresponding tissue biopsies via a phenol-chloroform extraction, rewritten into cDNA by reverse transcription and, correspondingly, in a TaqMan RT-PCR analysis according to the standard protocol on the relative content of the mineral corticoid receptor mineral corticoid ReceptorNA examined.
  • Commercially available primer / probe combinations from BD Biosciences for the mineral corticoid receptor and the control gene cyclophylin A were used as TaqMan probes.
  • MR shows a 2-3-fold increase in mRNA expression in endometriotic lesions (1 * -8 * , second group from left, black). If one compares healthy endometrium over different stages of the menstrual cycle, no difference in the expression levels can be seen (follokil phase compared to the luteal phase, third group from the right, white, compared to the second group from the right, light gray).
  • the endometrium of endometriosis patients does not differ in MR expression from the healthy patients (luteal phase endometriosis compared to luteal phase, 1st group from right, gray, opposite 2nd group from right, light gray).
  • Example 2 Example 2:
  • the lesions show markedly increased expression of the mineralocorticoid receptor in comparison to the control tissue (see in each case the expression of uterus control, lesion on the peritoneum and lesion on the intestine: a total of 4 animals were used in this experiment (numbers 14, 20, 26 and 32).
  • both lesions show an increased expression of the MR compared to the uterine control (black).
  • Nonhuman primates are the only species other than humans that spontaneously endometriosis under natural conditions form. They are therefore the most relevant model to study this disease.
  • rhesus macaques are implanted subcutaneously and interperitoneally for endometrial tissue in autologous transplantation for ovariectomy for reproducibility and after 60 days of either artificially induced menstrual cycle with either physiological concentrations of estradiol ( Control) or with a combination of estradiol and spironolactone (30 mg / kd / day).
  • the animals receive in this procedure a depot for estradiol substitution which allows a serum level of 80 to 100 pg / ml. In this way, it is ensured that the endometriotic lesions are exposed to physiological concentrations of estradiol. Depot can eliminate interindividual fluctuations in hormone levels and their impact on outcomes.
  • the size of the endometrial lesions was determined and in a histological analysis the proliferation in these lesions was detected.
  • animals treated with spironolactone show a significant reduction of endometriotic lesions (Table 1). Both the staining of the mitotic antigen Ki67 and the corresponding treatment with bromodioxyuridine (BrDU) show a reduction of the proliferation in the abdominal lesions (see Figure 3).
  • the mineral corticosteroid receptor antagonist spironolactone therefore has a positive effect on the genesis of endometriosis.

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Abstract

L'invention a pour objet l'utilisation d'antagonistes du récepteur de minéralocorticoïde pour la production d'un médicament servant au traitement de l'endométriose. L'invention concerne en particulier un agent thérapeutique amélioré contre l'endométriose présentant un profil efficacité/effet secondaire plus avantageux que les thérapies de traitement dont on dispose jusqu'à présent. Grâce à un antagoniste du récepteur de minéralocorticoïde, l'endométriose peut être traitée de façon durable sans entraîner de perte de la masse osseuse.
PCT/EP2008/052456 2007-03-02 2008-02-28 Antagonistes du récepteur de minéralocorticoïde pour le traitement de l'endométriose WO2008107373A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
EP08717238A EP2131825A1 (fr) 2007-03-02 2008-02-28 Antagonistes du récepteur de minéralocorticoïde pour le traitement de l'endométriose
CA002679520A CA2679520A1 (fr) 2007-03-02 2008-02-28 Antagonistes du recepteur de mineralocorticoide pour le traitement de l'endometriose
JP2009551220A JP2010520178A (ja) 2007-03-02 2008-02-28 子宮内膜症の治療のためのミネラルコルチコイド受容体アンタゴニスト
MX2009009332A MX2009009332A (es) 2007-03-02 2008-02-28 Antagonista del receptor de mineralocorticoides para el tratamiento de endometriosis.
BRPI0808427-0A BRPI0808427A2 (pt) 2007-03-02 2008-02-28 Antagonistas do receptor mineralcorticoide para o tratamento de endometriose
US12/529,447 US20110003778A1 (en) 2007-03-02 2008-02-28 Mineralcorticoid receptor antagonists for the treatment of endometriosis
AU2008223859A AU2008223859A1 (en) 2007-03-02 2008-02-28 Mineralcorticoid receptor antagonists for the treatment of endometriosis
IL200380A IL200380A0 (en) 2007-03-02 2009-08-13 Mineralcorticoid receptor antagonists for the treatment of endometriosis
ZA2009/06849A ZA200906849B (en) 2007-03-02 2009-10-01 Mineralcorticoid receptor antagonists for the treatment of endomertriosis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102007011105.5 2007-03-02
DE102007011105A DE102007011105A1 (de) 2007-03-02 2007-03-02 Mineralcorticoid-Rezeptor-Antagonisten zur Behandlung von Endometriose

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WO2008107373A1 true WO2008107373A1 (fr) 2008-09-12

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PCT/EP2008/052456 WO2008107373A1 (fr) 2007-03-02 2008-02-28 Antagonistes du récepteur de minéralocorticoïde pour le traitement de l'endométriose

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US (1) US20110003778A1 (fr)
EP (1) EP2131825A1 (fr)
JP (1) JP2010520178A (fr)
KR (1) KR20090119870A (fr)
CN (1) CN101621995A (fr)
AR (1) AR065585A1 (fr)
AU (1) AU2008223859A1 (fr)
BR (1) BRPI0808427A2 (fr)
CA (1) CA2679520A1 (fr)
DE (1) DE102007011105A1 (fr)
IL (1) IL200380A0 (fr)
MX (1) MX2009009332A (fr)
RU (1) RU2009136305A (fr)
TW (1) TW200900080A (fr)
WO (1) WO2008107373A1 (fr)

Cited By (4)

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WO2013064620A1 (fr) 2011-11-04 2013-05-10 Bayer Pharma Aktiengesellschaft 18-méthyl-6,7-méthylène-3-oxo-17-prégn-4-ène-21,17β-carbolactones, préparations pharmaceutiques contenant ces composés et leur utilisation dans le traitement de l'endométriose
WO2013160213A1 (fr) * 2012-04-23 2013-10-31 Bayer Pharma Aktiengesellschaft Utilisation intra-utérine de 18-méthyl-15 bêta, 16-bêta-méthylène-19-nor-20-spirox-4-en-3-ones, système intra-utérin contenant du 18-méthyl-15 bêta, 16-bêta-méthylène-19-nor-20-spirox-4-en-3-ones, et utilisation desdits composés pour la contraception et les traitements gynécologiques
WO2014086739A1 (fr) 2012-12-06 2014-06-12 Bayer Pharma Aktiengesellschaft Nouveaux dérivés du benzimidazole comme antagonistes ep4
US10730856B2 (en) 2013-12-19 2020-08-04 Bayer Pharma Aktiengesellschaft Benzimidazole derivatives as EP4 ligands

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BRPI1003661A2 (pt) * 2010-09-15 2013-01-08 Libbs Farmaceutica Ltda associaÇço farmacÊutica para tratar e/ou prevenir mioma e/ou endometriose, uso de resveratrol e progestogenio, composiÇço farmacÊutica para tratamento e/ou prevenÇço de mioma e/ou endometriose medicamento para tratamento e/ou prevenÇço de mioma e/ou endometrios, kit e mÉtodo para tratamento e/ou prevenÇço de mioma e/ou endometriose
US10311801B2 (en) * 2013-01-22 2019-06-04 Sharp Kabushiki Kaisha Liquid crystal display device

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Cited By (5)

* Cited by examiner, † Cited by third party
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WO2013064620A1 (fr) 2011-11-04 2013-05-10 Bayer Pharma Aktiengesellschaft 18-méthyl-6,7-méthylène-3-oxo-17-prégn-4-ène-21,17β-carbolactones, préparations pharmaceutiques contenant ces composés et leur utilisation dans le traitement de l'endométriose
WO2013160213A1 (fr) * 2012-04-23 2013-10-31 Bayer Pharma Aktiengesellschaft Utilisation intra-utérine de 18-méthyl-15 bêta, 16-bêta-méthylène-19-nor-20-spirox-4-en-3-ones, système intra-utérin contenant du 18-méthyl-15 bêta, 16-bêta-méthylène-19-nor-20-spirox-4-en-3-ones, et utilisation desdits composés pour la contraception et les traitements gynécologiques
WO2014086739A1 (fr) 2012-12-06 2014-06-12 Bayer Pharma Aktiengesellschaft Nouveaux dérivés du benzimidazole comme antagonistes ep4
US9708311B2 (en) 2012-12-06 2017-07-18 Bayer Pharma Aktiengesellschaft Benzimidazole derivatives as EP4 antagonists
US10730856B2 (en) 2013-12-19 2020-08-04 Bayer Pharma Aktiengesellschaft Benzimidazole derivatives as EP4 ligands

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TW200900080A (en) 2009-01-01
AU2008223859A1 (en) 2008-09-12
IL200380A0 (en) 2010-04-29
DE102007011105A1 (de) 2008-09-04
US20110003778A1 (en) 2011-01-06
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CN101621995A (zh) 2010-01-06
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